Peroxisome proliferators-activated receptors (PPARs) are members of the nuclear hormone receptor superfamily. There are three PPAR subtypes, which are the products of distinct genes and are commonly designated PPARα, PPARγ and PPARδ. Among them, PPARγ is the most extensively studied. Through heterodimerization with retinoid X receptors (RXRs), PPAR-RXR heterodimers bind to DNA-specific sequences called peroxisome proliferator response elements (PPREs), regulating the transcription of genes whose products are involved in lipid homeostasis, cell growth, and differentiation. Recent studies have shown that PPAR-γ is not only correlated to diseases such as obesity, insulin resistance, diabetes, hypertension, artherosclerosis, inflammation, but also potential target for treatment of ADPKD and cancer.
Hereditary forms of polycystic kidney disease (PKD) in humans are transmitted in either an autosomal recessive (ARPKD) or an autosomal dominant pattern (ADPKD), ADPKD, one of the most common, potentially lethal single-gene disorders, is the leading form of inherited kidney disorders. It is characterized by the accumulation of fluid-filled cysts in the cortex and medulla of bilateral kidneys and other organs like liver, seminal vesicles, pancreas and arachnoid membrane, causing extrarenal abnormalities such as intracranial aneurysms and dolichoectasias, dilatation of the aortic root, dissection of the thoracic aorta, mitral valve prolapse and abdominal wall hernias. It affects about 1:500 to 1:1000 people in all ethnic groups worldwide. In China, about 1,500,000 people have ADPKD, approximately 50% of people with it develop renal failure at the age of 60.
Since the genes responsible for ADPKD have been cloned and gene diagnosis, imaging detecting technologies have been developed quickly, prenatal/presymptomatic diagnosis has been possible clinically at present, more and more ADPKD sufferers could be diagnosed earlier without any clinical symptom or imageological changes. Currently, no effective treatment can prevent the cysts from forming or enlarging. Finding novel therapeutic interventions to delay the progression of PKD is an urgent task, researchers across the world are seeking novel drug targets all the time for treatment and prevention of ADPKD.
Muto et al have found that a PPAR-γ agonist pioglitazone, could prolong the lifespan of Pkd1−/− mices with ADPKD which usually die at the foetal period.
In vitro we firstly prove that PPAR-γ agonists 15d-PGJ2, rosiglitazone or pioglitazone could inhibit the proliferation and induce apoptosis of ADPKD cyst-lining epithelia in a dose-dependent and time-dependent manner, while the effect on human renal epithelial cells (HKC) is relatively weak. After administration of rosiglitazone on the Han:SPRD rats, the well documented animal model of ADPKD, treatment group had lesser proteinuria, kidney weight/body weight, blood urea nitrogen (BUN), cyst index, fibrosis score and inflammatory cells infiltration compared with control group by serological and histomorphometric analysis. The therapeutic mechanism seems not depend on it's metabolism regulation effect on serum glucose and lipid, but through inhibition of abnormal proliferation, apoptosis, interstitial inflammation and fibrosis. Long-term treatment shows rosiglitazone can prolong the survival of Han:SPRD rats (patent application number 200610023398.6). Considering the safety and efficacy of thiazolidinediones in treatment of animal model of ADPKD and type 2 diabetes patients clinically, PPAR-γ agonists may be effective in the treatment of ADPKD.
Thiazolidinediones are now widely used in the treatment of type 2 diabetes as PPAR-γ agonists, these include rosiglitazone, pioglitazone, troglitazone, et. Troglitazone was withdrawn in Europe and USA not long after it went on sale because of severe liver toxicity. Although rosiglitazone and pioglitazone show potent activity with less hepatotoxicity than troglitazone, they also have long-term side effects, such as hepatotoxicity, water-sodium retention, weight gain and possible exacerbation of congestive heart failure. In vivo, we also found that rosiglitazone-treated Han:SPRD rats demonstrated heart and liver weight gain with increased volume when they died, indicating that TZDs, administered chronically at high dose, could aggravate water-sodium retention and cardiac load, resulting in chronic congestive heart failure and hepatic congestion. Because multiple ADPKD patients merge with hyperpiesia and myocardial hypertrophy in midanaphase, the side effects of this kind of drugs, like aggravating congestive heart failure, challenges the clinical application in dealing with ADPKD. Since ADPKD sufferers generally need long-term administration or even lifelong medication, the drug safety is especially important and urgent in these patients.
Recently, researcher also have found that PPAR-γ is expressed in many cancers including the colon, breast, lung and prostate, and PPAR-γ ligands are generally antiproliferative in these settings. Specifically, PPAR-γ ligands inhibit the proliferation of human breast, prostate, colon and pituitary cancer cells in vitro. Thus PPAR-γ is considered to have potential antineoplastic effects both in solid cancers and in leukemia through inhibition of cell proliferation, induction of apoptosis and terminal differentiation or through inhibition of angiogenesis. Therefore, PPAR-γ ligands may represent a promising, novel therapeutic approach for certain human malignancies. On the other hand, it's evidenced by the fact that many people in the world are currently taking drug as PPAR-γ agonists for long-term control of type 2 diabetes. Thus, in the context of human cancer, it is important to note that PPAR-γ agonists are relatively nontoxic and well tolerated.
In sum, it is urgent to synthesize novel effective PPAR-γ agonists with less side effects in ADPKD and cancer treatment.